Escherichia coli strain and in Salmonella enterica serovar Typhimurium Brown PK,2001; Shiga toxin-encoding prophages have been observed to integrate at the mlrA gene of enterohemorrhagic E. coli Yokoyama K,2000.MlrA is a member of the MerR family, containing the conserved N-terminal DNA-binding domain present in members of this family Brown PK,2001; Ogasawara H,2010 On the other hand, its C-terminal, probably used by a yet-to-be-unidentified effector, showed no similarity to any of the hitherto-characterized MerR family members Ogasawara H,2010MlrA binds an AAAGTTGTACA(12N)TGCACAATTTT palindromic sequence and probably induces DNA underwinding, as in the case of MerR Ogasawara H,2010 Based on the site identified on the csgDp1 promoter, sites for another four genes were identified, two of which are transcriptional regulators Ogasawara H,2010 MlrA is found at a higher level in the hierarchy of the transcription factor network Ogasawara H, 2010; Ishihama A.,2010MlrA: MerR-like regulator A Brown PK,2001.Regulation of MlrA has been described Brown PK,2001; The mlrA gene is RpoS regulated in an avian pathogenic E. coli strain Brown PK,2001.; DNA binding; sequence-specific DNA binding transcription factor activity; transcriptional level; Transcription related; regulation of transcription, DNA-dependent; nucleotide binding; transcription, DNA-dependent

transcriptional repressor activity; negative regulation of transcription, DNA-dependent; positive regulation of transcription initiation, DNA-dependent; transcriptional level; Transcription related

Transcription related; activator; operon; molybdenum; ATP-binding cassette (ABC) transporter complex; molybdenum ion binding; hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances; molybdate ion transport; molybdate transmembrane-transporting ATPase activity; molybdate ion transmembrane transporter activity; transport; regulation of transcription, DNA-dependent; ATP binding; sequence-specific DNA binding transcription factor activity; DNA binding; transcription activator activity

nitrogen metabolism under nitrogen-limiting conditions Muse WB,1998The genes regulated by Nac are transcribed by RNA polymerase σ70; These genes are coupled to the nitrogen regulatory (Ntr) system, which is σ54 dependent, through Nac, whose transcription is activated by NtrC Muse WB,1998 Using DNA microarray analyses, it was shown that Nac could affect the expression of 25 genes Zimmer DP,2000 This transcriptional regulator is negatively autoregulated Muse WB,1998and is expressed under nitrogen-limiting conditions Camarena L,1998Nac belongs to the LysR family Muse WB,1998and features a helix-turn-helix motif located close to the N terminus Muse WB,1999 In contrast with most LysR family members, which are transcribed divergently from the gene they regulate, nac is distant on the genome from its regulated genes Muse WB,1998In Klebsiella pneumoniae, Nac functions as a dimer, and for some sites it can bind as a tetramer; it recognizes long and short sites in the absence of a coeffector Rosario CJ,2010; cytoplasm; Transcription related; repressor; activator; operon; nitrogen metabolism; negative regulation of transcription, DNA-dependent; specific transcriptional repressor activity; positive regulation of transcription, DNA-dependent; sequence-specific DNA binding transcription factor activity; transcription activator activity

system (PTS) Pennetier C,2008 Its function is to coordinate the biosynthesis of the amino sugars, D-glucosamine (GlcN) and N-acetylglucosamine (GlcNAc) with their catabolism Plumbridge JA.,1991; Plumbridge J.,2001; Plumbridge J,2004.The specific inducer for NagC is GlcNAc-6-P, the product of GlcNAc transport by the PTS Plumbridge JA.,1991; Plumbridge J.,2001 NagC is displaced from its DNA targets by interacting with GlcNAc-6-P Plumbridge JA.,1991Based on the structure of DgsA DNA-binding transcriptional repressor, models for the three-dimensional structure of NagC and for the binding of GlcNAc-6-P were developed Pennetier C,2008The Nag regulon consists of two divergent operons, nagE and nagBACD; nagC encodes the repressor of this regulon; Its localization within the inducible nagBACD operon is unusual, since most transcriptional dual regulators are located near the loci they control Plumbridge JA.,1991NagC is present at low levels within the bacterial cell Plumbridge JA.,1991The consensus sequence for the NagC-binding site has been determined via combination of native site comparisons, operator mutagenesis, and selection of DNA-binding fragments, Plumbridge J.,2001 The dual function of NagC requires it to bind simultaneously to two operators in order to form a DNA loop Plumbridge J.,2001 The strictly conserved TT/AA motif, located in both ends of the center of symmetry, is probably the major recognition point for NagC Plumbridge J.,2001NagC is a member of the ROK (repressor, ORFs, kinases) (NagC/XylR) family of proteins, which contains at least two distinct classes of proteins, xylose repressor (XylR) and a series of glucose/fructose kinases Titgemeyer F,1994; Hansen T,2002; NagC is similar to Mlc transcriptional dual regulator Cho S,2005 However, they have different specificities for select binding sites Plumbridge J.,2001.NagC has a helix-turn-helix motif in its N-terminal part Pennetier C,2008.; translation attenuation and efficiency; repressor; operon; activator; Transcription related; amino sugar conversions; transcription, DNA-dependent; regulation of transcription, DNA-dependent; carbohydrate metabolic process; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; cytoplasm

N-acetyl-neuraminic acid (or sialic acid) transport and metabolism Kalivoda KA,2003and in off-to-on switching of type 1 fimbriation; NanR is inactivated by N-acetyl-neuraminic acid Sohanpal BK,2004NanR is a member of the FadR/GntR family; Members of this family have two domains, an N-terminal domain with a helix-turn-helix DNA-binding motif and a C-terminal domain with dimerization and effector-binding motifs; Three-dimensional models of the N terminus of FadR and NanR show topological similarity and a ~26% sequence identity between them Kalivoda KA,2003NanR regulates transcription when it binds to a region of ~30 bp that contains three conserved motifs in tandem; However, this protein can be displaced from this region by N-acetyl-neuraminic acid; Although it has been shown that NanR can form homodimers in solution, its DNA-binding stoichiometry is unknown; When this protein is repressing transcription, it overlaps the whole promoter region Kalivoda KA,2003; Sohanpal BK,2004The region of 30 bp that NanR binds to is close to a Dam methylation site (GATC) Chu D,2008; Sohanpal BK,2004that appears to be necessary for induction of some genes of the NanR regulon Oshima T,2002 Methylation in these sites is prevented by NanR binding Chu D,2008; Sohanpal BK,2004; Transcription related; DNA binding; sequence-specific DNA binding transcription factor activity; intracellular; regulation of transcription, DNA-dependent; protein-DNA complex; transcription, DNA-dependent; operon; repressor

respiration; cytoplasm; intracellular signal transduction; sequence-specific DNA binding; regulation of transcription, DNA-dependent; transcription, DNA-dependent; intracellular; ATP binding; sequence-specific DNA binding transcription factor activity; DNA binding; nucleotide binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; repressor

binding; two-component signal transduction system (phosphorelay); intracellular; transcription, DNA-dependent; regulation of transcription, DNA-dependent; sequence-specific DNA binding; intracellular signal transduction; cytoplasm; anaerobic respiration; regulon; activator; two-component response regulator activity; two component regulatory systems (external signal); Transcription related; repressor

Na+ and it controls the transcription of the gene involved in adaptation to Na+ and alkaline pH Rahav-Manor O,1992; Carmel O,1994; Padan E,1993; Padan E,1999; Carmel O,1997; Padan E,1994; Rowbury RJ,1994; Padan E,1994 response to adverse conditions Sturny R,2003; Toesca I,2001 and biofilm formation Goller C,2006; Cerca N,2008 This regulator belongs to the LysR family; NhaR is composed of two domains: the amino-terminal domain, which contains the DNA-binding region, and the carboxy-terminal domain, which is possibly responsible for inducer binding Henikoff S,1988 In systematic studies of oligomerization, it was shown that some members of the LysR family, like NhaR, interact with other members of the family to form heterodimers, but the physiological significance of this is unknown Knapp GS,2010The binding targets for NhaR are 17 nucleotides long; Each dimer binds to one of these conserved sequences; The lengths of the degenerate binding sites of NhaR were defined according to the matrix shown for this regulator in the database RegPrecise, which contains matrices generated from alignments of orthologous regions Novichkov PS,2010.; activator; operon; pH; Transcription related; cytoplasm; transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity; regulation of transcription, DNA-dependent

the expression of several operonsencoding ribonucleotide reductases; The protein binds Zn2+ and contains ATP/dATPTorrents E,2007.NrdR was first identified as a potential regulator of ribonucleotide reductase genes by phylogenetic profilingRodionov DA,2005.nrdR is expressed at similar levels during exponential and stationary phase growth and is not required forgrowth Torrents E,2007.NrdR: nrd regulation Rodionov DA,2005Review: Herrick J,2007; repressor; metal ion binding; ATP binding; negative regulation of transcription, DNA-dependent; transcription repressor activity; double-stranded DNA binding; nucleotide binding

sulfur cluster binding; transcription, DNA-dependent; regulation of transcription, DNA-dependent; negative regulation of transcription, DNA-dependent; Transcription related; repressor; protein-DNA complex

metabolic process; detection of stimulus involved in sensory perception; nucleoside-triphosphatase activity; nitrogen fixation; transcription factor binding; regulation of transcription, DNA-dependent; intracellular; ATP binding; sequence-specific DNA binding transcription factor activity; glutamine; two component regulatory systems (external signal); DNA binding; nucleotide binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; transcription, DNA-dependent

cytoplasm; intracellular signal transduction; intracellular; regulation of transcription, DNA-dependent; DNA binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; transcription, DNA-dependent; transcription activator activity; transcription repressor activity

expression of antioxidant genes in response to oxidative stress, in particular, elevated levels of hydrogen peroxide; The OxyR regulon includes genes involved in peroxide metabolism, redox balance, and peroxide protection by, for example, manganese uptake Storz G,1990; Zheng M,2001; Mongkolsuk S,2002; Anjem A,2009 Moreover, OxyR activates the synthesis of the small, noncoding oxyS RNA; This allows OxyR to regulate as many as 40 additional gene products indirectly by affecting mRNA stability or translation efficiency Altuvia S,1997 OxyR acts as a repressor for its own synthesis in both the oxidized and reduced forms Christman MF,1989; Tao K,1991 In addition, expression of oxyR is positively regulated by cAMP-activated Crp protein during exponential growth and negatively regulated by RpoS when cells enter stationary phase Gonzalez-Flecha B,1997 Based on microarray assays, a new function as regulator of S-nitrosylation (a nitrosative stress regulon) under anaerobic conditions has been determined for OxyR Seth D,2012 and it is distinct from the OxyR regulon activated by oxidative stress Seth D,2012OxyR consists of 305 amino acid residues and is a member of the LysR family of bacterial transcription factors Christman MF,1989; Tao K,1989 It is a tetramer in solution Kullik I,1995 OxyR consists of two domains, the N-terminal domain, carrying a helix-turn-helix motif, and the C-terminal regulatory domain; A flexible linker connects both domains; The C-terminal domain contains the determinants for oligomerization and two redox-active cysteines, Cys199 and Cys208 Kullik I,1995; Lee C,2004; Zaim J,2003 OxyR functions as a reversible cellular redox switch; In the presence of 100 nM H2O2, activation occurs by the formation of an intramolecular disulfide bond between Cys199 and Cys208 Storz G,1990; Lee C,2004 Inactivation involves reduction of the disulfide bond by glutaredoxin 1 and glutathione Zheng M,1998 Oxidation is significantly faster than reduction, allowing for transient activation in a reducing environment Aslund F,1999 OxyR is also activated under nitrosative stress; this reaction involves S-nitrosylation of OxyR Hausladen A,1996 The crystal structures of the regulatory domain of OxyR in both its reduced and oxidized forms have been solved; Comparison of both structures reveals that oxidation is accompanied by a significant structural change in the regulatory domain Choi H,2001In systematic studies of oligomerization, it was shown that some members of the LysR family, like OxyR, interact with other members of the family to form heterodimers, but the physiological significance of this is unknown Knapp GS,2010OxyR recognizes a motif comprised of ATAGnt elements spaced at 10-bp intervals Toledano MB,1994 The binding to DNA differs significantly for the oxidized and reduced forms Toledano MB,1994 Reduced OxyR binds DNA at two pairs of major grooves separated by one helical turn, while oxidized OxyR occupies four consecutive major grooves; When bound to DNA, oxidized OxyR stimulates transcription by interacting with the C-terminal domain of the α-subunit of RNA polymerase Tao K,1995; other (mechanical, nutritional, oxidative stress); cytoplasm; regulon; activator; Transcription related; response to nitrosative stress; regulation of transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity; response to oxidative stress; transcription, DNA-dependent; transcription activator activity; transcription repressor activity; repressor

dehydrogenase complex Quail MA,1995; Haydon DJ,1993; Urbanowski ML,2000 Activity of PdhR is controlled by pyruvate; In the absence of this compound, the PdhR regulator binds to its target promoters; This repression is antagonized by its coeffector, pyruvate Quail MA,1995; Ogasawara H,2007 In addition to the role described above, PdhR also controls the synthesis of two key enzymes (Ndh and CyoA) in the terminal electron transport system Ogasawara H,2007The PdhR belongs to the GntR family of transcriptional regulatory proteins, which share sequence similarities in their N-terminal DNA-binding domains Haydon DJ,1991; Dong JM,1993 PdhR is negatively autoregulated Buck D,1989The pdhR consensus sequences has been determined to be 17bp Quail MA,1995 and more recently as 15 bp Ogasawara H,2007; cytoplasm; sequence-specific DNA binding transcription factor activity; intracellular; transcription activator activity; positive regulation of transcription, DNA-dependent; specific transcriptional repressor activity; negative regulation of transcription, DNA-dependent; Transcription related; activator; operon; repressor; glycolysis

Pho regulon in response to environmental Pi; The Pho regulon includes operons and genes whose products are involved in phosphorus uptake and metabolism Wanner BL.,1993; VanBogelen RA,1996; Baek JH,2006 Expression of the periplasmic binding proteins for peptide transport, OppA and DppA, is repressed by PhoB Smith MW,1992 In a proteomic analysis under phosphate-limiting conditions, it was found that up to 400 proteins are differentially expressed VanBogelen RA,1996 PhoB is also involved in bacterial virulence of pathogenic Escherichia coli Crepin S,2011PhoB is a response regulator and belongs to the two-component system PhoR/PhoB; Under phosphate limitation conditions the inner membrane sensor kinase PhoR autophosphorylates; Subsequent transfer of the phosphate group to PhoB results in activation of PhoB Makino K,1989 When phosphate is in excess, autophosphorylation of PhoR is inhibited and PhoB-P is dephosphorylated; This negative regulation requires in addition to PhoR an intact Pst system and PhoU Wanner BL.,1996 In the absence of PhoR, cross-regulation of PhoB by CreC or acetyl phosphate results in phosphorylation of PhoB in response to carbon sources Wanner BL,1992; Amemura M,1990; Baek JH,2007 PhoB consists of two functional domains, the N-terminal receiver domain, which is phosphorylated, and the C-terminal output domain, which binds to DNA and interacts with the σ70 subunit of RNA polymerase to activate transcription Makino K,1996; Makino K,1993 The output domain belongs to the winged helix-turn-helix family of transcription factors Martinez-Hackert E,1997 Its activity is silenced by the receiver domain, and phosphorylation relieves inhibition Ellison DW,2000 The 3D structure of the receiver domain Sola M,1999and of two constitutively active mutants of this domain Arribas-Bosacoma R,2007and the 3D structure of the output domain have been solved Martinez-Hackert E,1997PhoB binds to the Pho box, which has been described as two direct 11-bp repeats consisting of successive 7-bp direct repeats followed by an A/T-rich region of 4 bp, situated 10 bp upstream of the -10 region Makino K,1988; Blanco AG,2002; Makino K,1986 The pho promoters contain functional -10 sequences but lack the consensus -35 sequence Kimura S,1989The 3D structure of the PhoB effector domain in complex with its target DNA sequence reveals a novel tandem arrangement in which several monomers bind head to tail to successive 11-bp direct repeat sequences, coating one face of the double helix Blanco AG,2002; Bachhawat P,2005Based on DNA microarray analysis, it has been shown that PhoBR and PhoB are responsible for upregulation of phosphonate and glycerol phosphate metabolism and the high-affinity phosphate transport system, respectively, thus showing the complex regulation by the PhoR-PhoB two-component regulatory system Baek JH,2007; phosphorous metabolism; two-component response regulator activity; repressor; regulon; activator; Transcription related; cytoplasm; intracellular signal transduction; bacterial-type RNA polymerase holo enzyme binding; regulation of transcription initiation, DNA-dependent; phosphate ion transport; transport; regulation of transcription, DNA-dependent; transcription, DNA-dependent; DNA binding; two-component signal transduction system (phosphorelay); two component regulatory systems (external signal)

low Mg2+ environments and the control of acid resistance genes; Mediates magnesium influx to the cytosol by activation of mgtA; Promotes expression of the two-component regulatory system rstA/rstB and transcription of the hemL, mgrB, nagA, slyB, vboR and yrbL genes.; two component regulatory systems (external signal); repressor; operon; activator; Transcription related; cytoplasm; two-component response regulator activity; regulation of transcription, DNA-dependent; transcription, DNA-dependent; DNA binding; two-component signal transduction system (phosphorelay); intracellular signal transduction

purine biosynthesis; Transcription related; repressor; regulon; formyl-THF biosynthesis; amino acids; nitrogen metabolism; cytoplasm; regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; purine nucleotide biosynthetic process; nucleotide and nucleoside conversions

repressor and membrane-associated enzyme; The switch between the two activities is due to conformational changes triggered by proline binding; In the presence of proline, PutA is associated with the cytoplasmic membrane and acts a bifunctional enzyme catalyzing both reactions of the proline degradation pathway: the oxidation of proline by proline dehydrogenase and subsequent oxidation to glutamate by pyrroline-5-carboxylate (P5C) dehydrogenase; In the absence of proline, PutA is cytoplasmic and functions as a transcriptional repressor of the put regulon; The N-terminal 47 residues with a ribbon-helix-helix fold contain the dimerization domain and the specific DNA-binding activity of PutA Gu D,2004; Zhou Y,2008; Singh RK,2011; The Lys9 residue is essential for recognition of put promoter DNA Larson JD,2006; Crystal structures of this domain have been solved Larson JD,2006; In the absence of proline, PutA binds to operator sequences in the putA-putP intergenic region and represses transcription, most likely by keeping RNA polymerase from binding to the putA promoter Zhou Y,2008.The proline dehydrogenase activity resides in the amino-terminal 669 amino acids of PutA; a truncated protein retains proline dehydrogenase and DNA-binding activity but lacks membrane association and 1-pyrroline-5-carboxylate dehydrogenase activity Vinod MP,2002; Proline dehydrogenase activity requires the presence of an electron acceptor; in vivo, it is thought that the reduced FADH2 transfers electrons to the quinone pool in the cytoplasmic membrane, and finally to oxygen via the respiratory chain Abrahamson JL,1983; The proline:ubiquinone oxidoreductase reaction proceeds via a rapid equilibrium ping-pong mechanism with proline and ubiquinone binding at two distinct sites Moxley MA,2011; Association of the enzyme with the membrane is dependent on reduction of the FAD cofactor, which induces a change in the conformation of the protein Wood JM.,1987; Brown ED,1993; Zhu W,2003; Both proline binding and FAD reduction contribute to the conformational change Zhu W,2005; The membrane-associated form of PutA does not bind put promoter DNA; thus, the enzymatic and DNA-binding activities of PutA are mutually exclusive Zhang W,2004.Crystal structures of the amino-terminal proline dehydrogenase domain have been reported Lee YH,2003; Zhang M,2004; Zhang W,2007; Ostrander EL,2009; Srivastava D,2010, and site-directed mutants in various active site residues have been characterized Zhang M,2004; Baban BA,2004; These studies resulted in a detailed picture of the mechanism of the redox-dependent structural changes of the protein and identified Y540 as an important substrate specificity determinant; A solution structure of the entire protein show that PutA is a symmetric V-shaped dimer Singh RK,2011.The C-terminal domain shows similarity to aldehyde dehydrogenases, indicating that the true substrate for the second enzymatic activity may be γ-glutamic semialdehyde, which is thought to spontaneously equilibrate with P5C Ling M,1994.Based on studies using small-angle X-ray scattering (SAXS), two additional domains in the three-dimensional architecture of a trifunctional PutA have been reported: i) the DNA-binding domain (residues 1-49) has a ribbon-helix-helix (RHH) fold, and ii) the C-terminal domain (CTD) has ~200 bp that could function as a lid that covers the internal substrate-channeling cavity Singh RK,2011.Expression of putA is reduced by prolonged exposure to osmotic stress Deutch CE,1989.PutA: proline utilization Wood JM,1980Reviews: Maloy S,1993; Commichau FM,2008; proline biosynthetic process; glutamate biosynthetic process; DNA binding; 1-pyrroline-5-carboxylate dehydrogenase activity; proline dehydrogenase activity; transcription, DNA-dependent; cytoplasm; proline dehydrogenase; 1-pyrroline-5-carboxylate dehydrogenase; electron donors; amino acids; repressor; Transcription related; inner membrane; internal side of plasma membrane; bacterial-type RNA polymerase core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription; oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor; bacterial-type RNA polymerase core promoter proximal region sequence-specific DNA binding; flavin adenine dinucleotide binding; proline catabolic process to glutamate; oxidation-reduction process

that belongs to the multicomponent RcsF/RcsC/RcsD/RcsA-RcsB phosphorelay system Chen MH,2001; Castanie-Cornet MP,2007; Majdalani N,2005; Castanie-Cornet MP,2006; Gottesman S,1991and is involved in the regulation of the synthesis of colanic acid capsule, cell division, periplasmic proteins, motility, and a small RNA Huang YH,2006; Stout V.,; Jayaratne P,1993; Brill JA,1988; Wehland M,2000; Sledjeski DD,1996; Carballes F,1999; Gottesman S,1985; Stout V,1991; Sledjeski D,1995; Stout V.,1996; Francez-Charlot A,2003; Vianney A,2005; Fredericks CE,2006; Corbett D,2008; The response regulator RcsB is the principal regulator of this system and it may form complexes with the RcsA auxiliary protein (forming a heterodimer) Gottesman S,1991; Ogasawara H,2007; Ferrieres L,2007 while RcsB activates the others genes independently (in the form of a homodimer) Majdalani N,2005; Davalos-Garcia M,2001; Francez-Charlot A,2005; Boulanger A,2005; Majdalani N,2002; Gervais FG,1992RcsC is a sensor histidine kinase and is known to be a transmembrane protein composed of three domains: the external sensory domain (amino terminal), a cytoplasmic transmitter domain (carboxyl terminal), and a transmembrane hydrophobic central domain (unknown function); RcsC is a membrane-bound protein that is able to sense extracellular changes in temperature, overexpression of membrane protein, and osmolarity Mouslim C,2003; Sledjeski DD,1996 RcsC is a hybrid kinase, contains both an H1 and D1 domain, and is able to transfer phosphoryl groups to the conserved Hpt domain of RcsD Majdalani N,2005; Huang YH,2006; Majdalani N,2005 RcsC and RcsD are inner membrane proteins that are involved in the phosphorylation of RcsB in response to environmental signals Majdalani N,2005; Gupte G,1997; Schmoe K,2011 Once phosphorylated, the RcsB protein is a positive regulator and it increases the affinity for the specific DNA-binding sites and controls the transcriptional expression of operons Wehland M,2000; Majdalani N,2005 It is believed that RcsF protein may also be capable of phosphorylating RcsB.The RcsB/RcsA complex has major affinity for binding sites of which RcsB is only one; The homodimers of RcsB activate transcription, interacting with the RNA polymerase, by overlapping the -35 box of the core promoter; the central position of the binding site is located near bp -41.5 Majdalani N,2005; Majdalani N,2002 The formation of heterodimers between RcsB and the RcsA auxiliary protein stabilizes interactions with the distant binding sites Wehland M,2000; Ferrieres L,2007The amount of RcsA protein is limited both by its rapid degradation by two proteases, Lon and ClpYQ, and by its low level of synthesis Majdalani N,2005; Torres-Cabassa AS,1987; Dierksen KP,1996; Gottesman S,1991; Kuo MS,2004; Lee YY,2003 RcsB, which belongs to the two-component family, shows a helix-turn-helix motif for interaction with DNA in the C-terminal domain, while the the N-terminal domain is typical of the response regulator Majdalani N,2005Regulator protein RcsB is a member of the two-component regulatory system RcsC/RcsB Stout V.,; Brill JA,1988 It is involved in the activation of colanic acid capsule synthesis (cps) and cell division (ftsZ) genes Wehland M,2000; Carballes F,1999Based on its homology to other regulator proteins in E. coli, it is believed that the RcsB protein is activated through phosphorylation, probably by the sensor protein RcsC Gupte G,1997 However, direct phosphorylation of RcsB by RcsC has not been shown; The RcsF protein may also be capable of phosphorylating RcsB; Once activated, the RcsB protein is a positive regulator of capsule synthesis and cell division Wehland M,2000; Carballes F,1999 Regulator protein RcsB complexes with the RcsA protein (forming a heterodimer) for capsule synthesis activation Wehland M,2000; Stout V., RcsB activates the fts genes independently (in the form of a homodimer) Gervais FG,1992 RcsB is a member of the LuxR/UhpA protein family.Overproduction causes a drug resistance phenotype and affects transcription of genes involved in drug efflux Hirakawa H,2003.; colanic acid (M antigen); regulation of transcription, DNA-dependent; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; colanic acid biosynthetic process; transcription, DNA-dependent; transcription activator activity; transcription repressor activity; cytoplasm; two component regulatory systems (external signal); repressor; activator; capsule (M and K antigens); surface antigens (ECA, O antigen of LPS); operon; intracellular signal transduction; sequence-specific DNA binding; Transcription related

process; sequence-specific DNA binding; regulation of transcription, DNA-dependent; cytoplasm; Transcription related; activator; operon; carbon compounds; transcription, DNA-dependent

identity with MarA and SoxS Cohen SP,1993 These proteins activate a common set of about 50 target genes Barbosa TM,2000; Martin RG,2002; Martin RG,2003; Pomposiello PJ,2001 the marA/soxS/rob regulon, involved in antibiotic resistance Martin RG,1996; Griffith KL,2005; Ariza RR,1995 superoxide resistance Jair KW,1996; Nunoshiba T,1992; Wu J,1992 and tolerance to organic solvents White DG,1997; Aono R.,1998and heavy metals Nakajima H,1995 The activity of each protein is induced by different signals: the activity of Rob is increased with dipyridyl, bile salts, or decanoate Rosner JL,2002; Rosenberg EY,2003 and the activities of MarA and SoxS are increased by the aromatic weak acid salicylate Pomposiello PJ,2001and oxidative stress Demple B.,1996 respectively; Many genes are regulated by all three proteins; however, some genes are regulated by only one of them; The differential regulation of these genes might be caused by the degeneracy of their DNA-binding sites Pomposiello PJ,2003 Rob, MarA, and SoxS bind as monomers to the same DNA site, a degenerate 20-bp sequence known as the Mar-Sox-Rob box, which has to be in a specific orientation and distance relative to the -35 and -10 boxes of the promoter Martin RG,1999; Wood TI,1999 In class I promoters, the activators bind upstream of the -35 box and are generally oriented in the backward direction, while in class II promoters the proteins overlap the -35 promoter hexamer and generally are oriented in the forward direction Martin RG,1999; Wood TI,1999 As a subset of the class I promoters, the Mar-Sox-Rob box is separated by ~30 bp from the -10 hexamer but can be functional in either orientation Martin RG,1999; Wood TI,1999The Mar-Sox-Rob box contains an invariant A at position 1, two recognition elements, the RE1 at position 4-7 and RE2 at position 15-18, and a 7-bp A/T-rich spacer separating these elements Kwon HJ,2000; Dangi B,2001; Griffith KL,2001 There are more than 10,000 such binding sites per genome Griffith KL,2002 However, the majority of these sites are not functional because they are not in the proper orientation or distance relative to the promoter Martin RG,2002 It was proposed that these proteins bind to their target sites by a mechanism named DNA scanning or prerecruitment; In prerecruitment, the protein first binds to RNA polymerase in solution, and the binary complex then scans the DNA to find its binding sites Martin RG,2002; Griffith KL,2002 Rob consists of two domains and belongs to the AraC/XylS family Gallegos MT,1997 The N-terminal domain is the DNA-binding domain and is homologous to MarA and SoxS and the C-terminal domain of AraC; It carries two helix-turn-helix (HTH) motifs for DNA binding; One of them, located in the N-terminal region, interacts with the element RE1 of the Mar-Sox-Rob box, and the HTH located in the C-terminal region interacts with RE2 Griffith KL,2002; Rhee S,1998; Dangi B,2001 In the case of Rob, it appears that only one of the two HTH motifs makes base-specific contacts with DNA Kwon HJ,2000 The crystal structures of Rob Kwon HJ,2000and MarA Rhee S,1998in complex with DNA and the solution structure of the DNA-binding domain of AraC Rodgers ME,2009have been solved.The C-terminal domain of Rob is similar to a portion of the enzyme GalT Kwon HJ,2000 It regulates the activity of Rob by a sequestration-disposal mechanism, that is, it mediates the sequestration of Rob into intracellular foci; Sequestered Rob is inactive; Upon addition of the inducer, Rob is released in its active form Griffith KL,2009 The C-terminal domain blocks in addition proteolytic degradation by Lon protease Griffith KL,2009rob appears to be transcribed abundantly at 5,000-10,000 molecules per cell Skarstad K,1993; Ali Azam T,1999 throughout the growth cycle; rob expression is enhanced at the stationary phase and under glucose and phosphate starvation, and it was suggested that expression of rob is σS dependent Kakeda M,1995 Reviews: Alekshun MN,1999; Demple B.,1996; Randall LP,2002; DNA replication; Transcription related; nucleoproteins, basic proteins; activator; regulon; cytoplasm; sequence-specific DNA binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; DNA-dependent DNA replication; regulation of transcription, DNA-dependent

transcription, DNA-dependent; DNA binding; two-component signal transduction system (phosphorelay); two-component response regulator activity; two component regulatory systems (external signal); activator

of pyrimidine metabolism Loh KD,2006; Shimada T,2007and also plays a role in regulation of the genes for degradation of purines and genes for maintenance of pH homeostasis Shimada T,2007This protein belongs to the TetR family, whose members have an N-terminal DNA-binding domain that contains a helix-turn-helix motif and a C-terminal domain for dimerization and ligand binding Ramos JL,2005RutR recognizes and binds a 16-bp (7-2-7) inverted repeat consensus sequence Shimada T,2007; Shimada T,2008 where the central A/T nucleotide in each half-site appears to be the most important for the site Shimada T,2008 This binding is inhibited when uracil and thymine bind to RutR, although the effect is greater for uracil than for thymine Shimada T,2007It has been demonstrated, in E. coli as in other bacteria, that RutR binds to several coding regions located hundreds of base pairs downstream of the start codon; However, no role in transcriptional regulation of this binding has been observed Shimada T,2008.The rutR gene, which is autorepressed Shimada T,2007 is transcribed divergently from the RutR-regulated rutABCDEFG operon Loh KD,2006.RutR: pyrimidine utilization, rut repressor Loh KD,2006; sequence-specific DNA binding transcription factor activity; repressor; operon; Transcription related; negative regulation of transcription, DNA-dependent; positive regulation of transcription, DNA-dependent; transcription activator activity; specific transcriptional repressor activity

although little is known about the regulator role of SlyA; It has been demonstrated that SlyA increases expression of hemolysin E by antagonizing the negative effects of H-NS Ludwig A,1999; Wyborn NR,2004 SlyA belongs to the MarR family of transcriptional regulators; This protein consist of two domains, an amino-terminal domain involved in dimerization and a carboxy-terminal domain indispensable for DNA recognition Wu RY,2003 It is known that SlyA recognizes a short palindromic DNA sequence of 12 bp Wyborn NR,2004; pathogenesis; regulation of transcription, DNA-dependent; cytoplasm; Transcription related; activator; operon; cell killing; intracellular; transcription activator activity; transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity

of superoxide and nitric oxide and protection from organic solvents and antibiotics Demple B.,1996; Semchyshyn H,2005; Lee JH,2009; Nunoshiba T,1992; Amabile-Cuevas CF,1991; Li Z,1994; White DG,1997SoxS shares 49% identity with MarA and the N-terminal domain of Rob Cohen SP,1993 These proteins activate a common set of about 50 target genes Barbosa TM,2000; Martin RG,2002; Martin RG,2003; Pomposiello PJ,2001 the marA/soxS/rob regulon, involved in antibiotic resistance Martin RG,1996; Griffith KL,2005; Ariza RR,1995 superoxide resistance Jair KW,1996; Wu J,1992 and tolerance to organic solvents White DG,1997; Aono R.,1998and heavy metals Nakajima H,1995 The activity of each protein is induced by different signals: the activity of Rob is increased with dipyridyl, bile salts, or decanoate Rosner JL,2002; Rosenberg EY,2003 and the activities of MarA and SoxS are increased by the aromatic weak acid salicylate Pomposiello PJ,2001and oxidative stress Demple B.,1996 respectively; Many genes are regulated by all three proteins; however, some genes are regulated by only one of them; The differential regulation of these genes might be caused by the degeneracy of their DNA-binding sites Pomposiello PJ,2003SoxS, MarA, and Rob bind as monomers to the same DNA site, a degenerate 20-bp sequence known as the Mar-Sox-Rob box, which has to be in a specific orientation and distance relative to the -35 and -10 boxes of the promoter Martin RG,1999; Wood TI,1999 In class I promoters, the activators bind upstream of the -35 box and are generally oriented in the backward direction, while in class II promoters the proteins overlap the -35 promoter hexamer and generally are oriented in the forward direction Martin RG,1999; Wood TI,1999 As a subset of the class I promoters, the Mar-Sox-Rob box is separated by ~30 bp from the -10 hexamer but can be functional in either orientation Martin RG,1999; Wood TI,1999The Mar-Sox-Rob box contains an invariant A at position 1, two recognition elements, the RE1 at position 4-7 and RE2 at position 15-18, and a 7-bp A/T-rich spacer separating these elements Kwon HJ,2000; Dangi B,2001; Griffith KL,2001 There are more than 10,000 such binding sites per genome Griffith KL,2002 However, the majority of these sites are not functional because they are not in the proper orientation or distance relative to the promoter Martin RG,2002 It was proposed that these proteins bind to their target sites by a mechanism named DNA scanning or prerecruitment; In prerecruitment, the protein first binds to RNA polymerase in solution, and the binary complex then scans the DNA to find its binding sites Martin RG,2002; Griffith KL,2002 It has been shown that SoxS binds to the C-terminal domain of the α-subunit of RNA polymerase (α-CTD), in particular, it interacts with amino acid residues lying in or near the DNA-binding determinant of α-CTD; Apparently, SoxS functions as a co-sigma factor and redirects RNA polymerase to promoters carrying a SoxS-binding site Shah IM,2004 A new interaction that also occurs via prerecruitment between σ70 R4 of RNApolymerase (RNAP) and SoxS has been identified Zafar MA,2010; There is evidence for theexistence of two types of interactions between SoxS and σ70 R4, with one type being able to occur off-DNA (within a SoxS-RNAP binary complex that scans the chromosome for SoxS-dependent promoters) and with the other one occurring on-DNA (within a SoxS-RNAP binary complex residing at a SoxS-dependent promoter) Zafar MA,2010; SoxS is now the first example of an Escherichia coli transcriptional activator that uses a single positive control surface to make specific protein-protein contacts with two different subunits of RNAP Zafar MA,2010; In class I promoters, the σ70 R4 region binds to the -35 box and SoxS binds upstream of the hexamer, but in class II promoters SoxS binds to the -35 box, occluding the binding of σ70 R4 Zafar MA,2010SoxS, MarA, and Rob belong to the AraC/XylS family of transcriptional regulators Gallegos MT,1997and, like other members of this family, they have two helix-turn-helix (HTH) motifs for DNA binding: one of them, located in the N-terminal region, interacts with the element RE1 of the Mar-Sox-Rob box, and the HTH located in the C-terminal region interacts with the element RE2 Griffith KL,2002; Rhee S,1998; Dangi B,2001soxS is divergently transcribed from soxR Wu J,1991 SoxR is the transcriptional activator for soxS and a sensor for superoxide and nitric oxide through its [2Fe-2S] center; It activates soxS transcription when oxidized Gaudu P,1996; Hidalgo E,1997 soxS is regulated only by its intracellular concentration; Upon removal of the inducer, SoxS is degraded by the Lon protease Griffith KL,2004 The binding of SoxS with DNA or RNA polymerase protects it from degradation Shah IM,2006Transcriptomic and statistical modeling analyses with Zn concentration shifts showed a transient change in the activity of the iron regulator Fur and of the oxidative stress regulator SoxS; these findings suggest a competitive binding mechanism for the physiology of Zn and Fe uptake Graham AI,2012Reviews: Poole RK.,2005; Touati D.,2000; Cabiscol E,2000; Demple B.,1996; other (mechanical, nutritional, oxidative stress); cytoplasm; repressor; regulon; activator; Transcription related; regulation of transcription, DNA-dependent; sequence-specific DNA binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription repressor activity; response to oxidative stress; xenobiotic metabolic process; transcription, DNA-dependent; transcription activator activity; detoxification

regulator activity; two-component signal transduction system (phosphorelay); DNA binding; regulation of transcription, DNA-dependent; repressor; two component regulatory systems (external signal); anaerobic respiration; operon

cytoplasm; tryptophan; Transcription related; repressor; operon; sequence-specific DNA binding; regulation of transcription, DNA-dependent

regulon Wallace BJ,1969; Brown KD,1971; Pittard J,2005 The TyrR regulon involves genes that are essential for aromatic amino acid biosynthesis and transport; TyrR can act both as a repressor and as an activator of transcription at σ70-dependent promoters Pittard AJ,1991TyrR is a homodimer in solution; In the presence of tyrosine and ATP it self-associates to form a hexamer Wilson TJ,1994; Dixon MP,2002 TyrR consists of three functional domains, an N-terminal domain (aa 1-190), a central domain (aa 206-433), and a C-terminal domain (aa 444-513); The structure of the N-terminal domain has been solved Verger D,2007 It contains both an ACT and a PAS domain and is responsible for the activation functions of TyrR; The central domain carries an AAA+ domain typical for enhancer-binding proteins Swarbrick JD,2002 This domain is responsible for the binding and hydrolysis of ATP and for the ATP-dependent binding of the aromatic amino acid cofactors; In addition it possesses a phosphatase activity that is stimulated by zinc ions and inhibited by L-tyrosine and ATP Zhao S,2000 The central domain is responsible for the repressor functions of TyrR and contains determinants important for the hexamerization Dixon MP,2002 The C-terminal domain carries a classic HTH motif and is involved in DNA binding and dimerization Yang J,1993; Wang Y,2001TyrR binds specifically to an 18-bp palindromic target sequence, the Tyr box Kasian PA,1986; Pittard AJ,1991 TyrR binds to strong boxes in the absence of any cofactors; Binding to weak boxes requires ATP, tyrosine, or in the case of tyrB tyrosine or phenylalanine, and an adjacent strong box Pittard AJ,1991; Yang J,2002 TyrR can act as a transcriptional activator and repressor; Repression requires ATP-dependent binding of aromatic amino acids to the central domain with one exception: TyrR represses its own transcription without additional cofactors; Tyrosine is the major effector of TyrR-mediated repression; Some repression occurs with phenylalanine as a cofactor in the case of aroF Brown KD,1971 aroL Lawley B,1994 tyrP and aroP Whipp MJ,1977 and aroG Davies WD,1985or with tryptophan as a cofactor for aroL Lawley B,1994and aroP Whipp MJ,1977 Activation appears to involve non ATP-dependent binding of phenylalanine, tyrosine, or tryptophan to the N-terminal domain of TyrR and the binding of TyrR to a strong box located upstream of the ?35 region of the promoter; TyrR activates transcription by interacting with the C-terminal domain of the α-subunit of polymerase Lawley B,1995; aromatic compound catabolic process; signal transducer activity; DNA binding; nucleotide binding; two-component signal transduction system (phosphorelay); ATP binding; intracellular; signal transduction; transcription factor binding; nucleoside-triphosphatase activity; operon; cytoplasm; protein-DNA complex; negative regulation of transcription, DNA-dependent; regulation of transcription, DNA-dependent; transcription, DNA- dependent; Transcription related; activator; repressor

is expressed constitutively and that coordinately represses transcription of a divergent operon (ula) involved in transport and utilization of L-ascorbate catabolism Zhang Z,2003; Campos E,2002; Campos E,2007; Hvorup R,2003 Synthesis of these genes is induced when Escherichia coli is grown in the absence of glucose, and under anaerobic conditions it can ferment L-ascorbate; under aerobic conditions it is functional in the presence of casein acid hydrolysate Campos E,2004; Yew WS,2002; Campos E,2007 L-Ascorbate-6-P is the effector of the UlaR transcriptional repressor, and when this small molecule binds to UlaR, it severely impairs the formation of UlaR cognate operator sites, since they form a stable complex Garces F,2008 L-Ascorbate-6-P weakens the affinity of UlaR for DNA and displaces the UlaR oligomer state from a transcription-silencing tetrameric form to a transcription-activating dimeric form Garces F,2008 UlaR activity is also controlled by homotypic tetramer-dimer transitions regulated by L-ascorbate-6-P Garces F,2008 UlaR binds to four inverted repeat motifs in the divergent intergenic region ulaG-ulaA and overlaps its target promoters to repress transcription by blocking the interaction of the RNA polymerase with ulaGp and ulaAp Campos E,2004 Here, the presence of L-ascorbate-6-P breaks this configuration down into DNA-free UlaR homodimers and allows transcription to proceed Garces F,2008 At concentrations of >2 nM, L-ascorbate-6-P displaces UlaR from its operator site Garces F,2008In this system the full repression of the ula regulon requires IHF and binding of UlaR to four operator sites, possibly involving UlaR-mediated DNA loop formation Campos E,2004 The UlaR transcriptional repressor belongs to the DeoR family, and accordingly, this transcriptional repressor family protein is composed of two domains: an N-terminal HTH domain (residues 1-62), which contains the DNA-binding region Campos E,2002 and the C-terminal sugar- phosphate-binding domain (residues 69-251), which is responsible for dimerization and inducer binding Anantharaman V,2006 The C-terminal sugar-phosphate-binding domain belongs to the DeoR-C family of the ISOCOT superfamily and is structurally related to E. coli D-ribose-5-P isomerase Anantharaman V,2006 Asp206 and Lys209 are directly involved in binding L-ascorbate-6-P Garces F,2008Review: Amouyal M.,2005.; Transcription related; L-ascorbic acid binding; regulation of transcription, DNA-dependent; transcription repressor activity; intracellular; protein binding; transcription, DNA-dependent; DNA binding; sequence-specific DNA binding transcription factor activity; repressor; cytoplasm

regulates its own synthesis, and in the absence of fructuronate it represses transcription of the cluster of operons involved in transport and degradation of the sugar acids β-D-glucuronides, glucuronate, and gluconate Ritzenthaler P,1982; Robert-Baudouy J,1981; Rodionov DA,2000; Bates Utz C,2004; Blanco C,1986 This regulator is subject to catabolic repression in the presence of glucose and at low levels of cyclic AMP.Although little is known about the regulating mechanism of UxuR, it has been shown to act as a repressor, binding to a putative inverted repeat sequence from the uid operon in a cooperative process with UidR Ritzenthaler P,1983; Blanco C,1986; Blanco C.,1987 In 1986, Blanco et al; proposed that total repression of UxuR is achieved in the presence of UidR, suggesting the possibility that UxuR and UidR form a complex; Independently, each repressor binds to DNA separately Blanco C,1986; Blanco C,1985; Blanco C.,1987; On the other hand, UxuR is highly similar to ExuR (49% identity), and apparently both act together, capable of cross talk to regulate expression of the uxuR regulon Rodionov DA,2000.UxuR is a protein that belongs to the GntR family and participates as a regulator of several genes involved in carbon uptake.; carbon compounds; repressor; operon; Transcription related; cytoplasm; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; transcription, DNA-dependent; transcription repressor activity; regulation of transcription, DNA-dependent

It coregulates with CRP, a global transcriptional regulator Song S,1997 These regulators bind cooperatively to activate transcription of operons involved in transport and catabolism of d-xylose; Synthesis of these operons is induced when Escherichia coli is grown on d-xylose in the absence of glucose; Gene induction occurs when the physiological inducer, d-xylose, binds to XylR and when cellular cyclic AMP levels are high Song S,1997In the presence of d-xylose, XylR binds in tandem to four inverted repeat sequences in the xylAB/xylFGHR intergenic region to activate transcription by overlapping the ?35 boxes of xylABp and xylFGHRp Song S,1997 The binding targets for XylR consist of 18-nucleotide-long directed repeat sequences that possess conserved motifs; each monomer binds to one of these conserved sequences Song S,1997; Laikova ON,2001 XylR belongs to the AraC/XylS family Gallegos MT,1997; Tobes R,2002; carbon compounds; operon; activator; Transcription related; cytoplasm; transcription, DNA-dependent; sequence-specific DNA binding; intracellular; sequence-specific DNA binding transcription factor activity; DNA binding; regulation of transcription, DNA-dependent